A nerve growth factor (NGF) is one of humoral factors called generally “neurotrophic factors”, and plays an important role in generation and differentiation of neurons and in maintaining functions of neurons in the body. As NGF receptors, a high affinity trkA receptor (receptor-type tyrosine kinase) and a low affinity p75NTR receptor are known. There is a report reporting that among these, the p75NTR binds to all of the neurotrophic factors and is involved in apoptosis in the process of neuronal generation. However, the role of the p75NTR has not yet been sufficiently explained. Meanwhile, it is known that knockout mice of the NGF and the trkA receptor express the same phenotype (Non-Patent Document 1), and it is considered that the physiological action of NGF is expressed mainly via the trkA receptor.
In 1993, there was a report reporting that the administration of NGF to rats induced pain (Non-Patent Document 2), and since then, there has been a report reporting that intravenous administration of NGF to human beings induces systemic myalgia and that topical administration of NGF exerts a systemic effect and induces hyperpathia and allodynia in an injection site (Non-Patent Document 3). In addition, there is a report reporting that a knockout mouse of the trkA receptor shows analgesia (Non-Patent Document 4), so it is considered that NGF is a molecule deeply involved in the expression of pain. Regarding the correlation between NGF and the pathological condition of human pain, it has been demonstrated that expression of NGF/trkA is accelerated in articular cartilages with osteoarthritis (OA) (Non-Patent Document 6) and that the level of NGF is increased in patients with rheumatoid arthritis (Non-Patent Document 7) or interstitial cystitis (Non-Patent Document 8).
From the above facts, it is expected that if a monoclonal antibody which specifically binds to NGF and has an inhibitory activity against the action of NGF can be developed, this will be useful for treating, preventing, and diagnosing various diseases including pain relating to NGF.
As anti-human NGF antibodies which have been clinically developed so far, tanezumab (Patent Document 1) and PG110 (Patent Document 2) as humanized anti-human NGF antibodies, and REGN475 (Patent Document 3), fulranumab (Patent Document 4), and MEDI-578 (Patent Document 5) as fully human anti-human NGF antibodies have been reported. Among these, tanezumab is being most briskly developed by priority, and there is a report reporting that according to clinical test results, this antibody exerts a potent and extensive analgesic effect on pain such as arthralgia accompanied by osteoarthritis, chronic back pain, and cystalgia accompanied by interstitial cystitis (Non-Patent Documents 9 to 11).
Generally, as main factors determining an effective dose of an antibody drug, the neutralizing activity of an antibody against an antigen and the amount of antigens present in the body are exemplified. Improving the neutralizing activity leads to the decrease of dose, and consequently, this can be mentioned as very useful amelioration leading to decrease in the financial burden of patients and medical costs. If the decrease in dose can be realized, subcutaneous administration can also be carried out. Subcutaneous administration has a major advantage that a patient can perform self-injection at home if certain conditions are satisfied. In addition, while the antibody drug is generally administered via drips for a certain time in many cases in the intravenous administration, the drug can be administered as a bolus in the subcutaneous administration, which is another advantage. Both the physician and the patient can select a preparation for intravenous administration and a preparation for subcutaneous administration, and this is a desirable factor. However, in the subcutaneous administration, a dose that can be given per administration is as small as about 1 mL in general, so a sufficient amount of antibodies need to be included in the dose so as to express the drug efficacy. Moreover, unlike the intravenous administration, bioavailability needs to be considered for the subcutaneous administration. That is, in order to realize a preparation for subcutaneous administration, it is required to prepare an antibody which exhibits excellent solubility and expresses a sufficient drug efficacy even at a small dose. Accordingly, if an antibody which has a higher neutralizing activity against NGF compared to the antibodies in the related art is obtained, this will be useful for treating diseases relating to NGF and for improving convenience of the treatment.
As described above, though NGF is an important factor for growth of neurons, performing sufficient examination in terms of safety is necessary in developing medical drugs that inhibit the function of NGF. Particularly, as one of the respects which should be examined in terms of safety, the effects on a fetus are exemplified. So far, regarding the functional inhibition of NGF, there have been reports reporting that NGF mutation is the cause of congenital analgesia (Non-Patent Document 5), and that in an animal experiment, when a pregnant guinea pig is caused to produce an autoantibody to NGF so as to inhibit NGF in the body, the newborn guinea pig shows symptoms of analgesia (Non-Patent Document 12). Moreover, in a test using NGF- or trkA-deficient mice, it has been demonstrated that deficiency of NGF action inhibits the growth of neurons of sensory nerves and sympathetic nerves in an embryo (Non-Patent Documents 4 and 13). From these results, it is understood that NGF is an essential factor of neurodevelopment in the early stage of development. The NGF-related diseases also include diseases that women at a child-bearing age suffer from at a high rate, such as interstitial cystitis (half or more of the patients are 44 years old or younger, and 90% of patients are females (Non-Patent Document 14)), chronic back pain (an average age of 40 to 50, and 50% of patients are females (Non-Patent Documents 15 to 17)), and migraine (a peak age of onset ranges from 15 to 40 years, and 80% of patients are female (Non-Patent Document 18)). In this situation, in developing the anti-NGF antibody as a medical drug, it is very important to avoid the risk of side effects on a fetus in pregnant women.
As another risk factor in a case of developing the anti-NGF antibody as a medical drug, immunocomplex (IC) formation is exemplified. The immunocomplex which is a combination of an antigen and an antibody is generally treated in a reticuloendothelial system such as the spleen or the liver. However, it has been reported that when a pathological condition such as immune abnormality is caused or when the size of the formed IC is large, the IC loses solubility, which relates to the increase of the risk of thrombus formation and to the onset of nephritis caused by the glomerular accumulation of the IC. Though IgG is a bivalent antibody, when an antigen is polyvalent, the IC may have various sizes due to lattice formation. The size of the IC depends on the amount of an antibody and an antigen and the ratio therebetween, affinity of an antibody, and the like. For example, an anti-VEGF antibody bevacizumab (product name: Avastin) is an IgG1 antibody, and there is a report reporting that this antibody forms an IC by binding to a dimer VEGF and induces thrombus formation. Specifically, when Avastin and VEGF are administered to a human FcγRIIα receptor Tg mouse, formation of a pulmonary artery thrombus is observed (Non-Patent Document 19). In addition, there is a report reporting that an arterial thrombus is formed at a higher rate in patients with metastatic cancer who receive chemotherapy with Avastin treatment, compared to a placebo group receiving only chemotherapy (Non-Patent Document 20). Since NGF also forms a dimer in the body to exert physiological activity, it is desirable to further improve safety by avoiding the risk of IC formation in developing a medical drug of the anti-NGF antibody.
Furthermore, at the Phase 3 clinical trial of Tanezumab, some of patients exhibited joint-related adverse event which is mainly rapid progressive osteoarthritis (RPOA). This adverse event was also observed at the Phase 2 clinical trial of Fulranumab (Non-Patent Document 21 and 22). In this context, the clinical trials of anti-NGF antibody in United States were suspended on the recommendation of Food and Drug Administration (FDA). Then, in developing the anti-NGF antibody as a medical drug, it is also desirable to decrease the risk of joint-related adverse events such as RPOA in light of safety.
For the above reasons, for treating or preventing various NGF-related diseases, it is very important to obtain an anti-NGF antibody which is excellent in safety by reducing the risk of side effects such as the effects on a fetus, thrombus formation, and joint-related adverse events such as RPOA while maintaining a high neutralizing activity.